This application is a 371 of PCT/FR00/00814 filed Mar. 31, 2000.
A subject, of the present invention is new derivatives of lipoic acid, which have an inhibitory activity on NO-synthase enzymes producing nitrogen monoxide NO and/or are agents which allow the regeneration of antioxidants or entities which trap the reactive oxygen species (ROS) and which intervene in a more general fashion in the redox status of thiol groups. These antioxidants or entities which trap the reactive oxygen species can be of natural origin, such as for example vitamin E or glutathione, or of synthetic origin such as certain products which trap the ROS or products having both an inhibitory activity on NO-synthase enzymes and an activity which traps the ROS. Examples of such products of synthetic origin can in particular be found in the PCT Patent Applications WO 96/09653, WO 98/42696 and WO 98/58934.
Therefore, the invention relates in particular to the derivatives corresponding to general formula (I) defined below, their preparation methods, the pharmaceutical preparations containing them and their use for therapeutic purposes, in particular their use as NO-synthase inhibitors and/or as agents which allow the regeneration of antioxidants or entities which trap the ROS""s and which intervene in a more general fashion in the redox status of thiol groups.
Given the potential role of NO and the ROS""s and the metabolism of glutathione in physiopathology, the new derivatives described corresponding to general formula (I) may produce beneficial or favourable effects in the treatment of pathologies where nitrogen monoxide and the metabolism of glutathione as well as the redox status of thiol groups are involved. In particular:
cardiovascular and cerebrovascular disorders including for example atherosclerosis, migraine, arterial hypertension, septic shock, ischemic or hemorragic cardiac or cerebral infarctions, ischemias and thromboses.
disorders of the central or peripheral nervous system such as for example neurodegenerative diseases where there can in particular be mentioned cerebral infarctions, sub-arachnoid haemorrhaging, ageing, senile dementias including Alzheimer""s disease, Huntington""s chorea, Parkinson""s disease, Creutzfeld Jacob disease and prion diseases, amyotrophic lateral sclerosis but also pain, cerebral and bone marrow traumas, addiction to opiates, alcohol and addictive substances, erective and reproductive disorders, cognitive disorders, encephalopathies, encephalopathies of viral or toxic origin, depression, anxiety, schizophrenia, epilepsy, sleeping disorders, eating disorders (anorexia, bulimia etc.);
disorders of the skeletal muscle and neuromuscular joints (myopathy, myositis) as well as cutaneous diseases.
proliferative and inflammatory diseases such as for example atherosclerosis, pulmonary hypertension, respiratory distress, glomerulonephritis, cataracts, portal hypertension, psoriasis, arthrosis and rheumatoid arthritis, fibroses, amyloidoses, inflammations of the gastro-intestinal system (colitis, Crohn""s disease) or of the pulmonary system and airways (asthma, sinusitis, rhinitis) as well as contact or delayed hypersensitivities;
organ transplants.
auto-immune and viral diseases such as for example lupus, AIDS, parasitic and viral infections, diabetes and its complications including retinopathies, nrephropathies and polyneuropathies, multiple sclerosis, myopathies;
cancer.
autosomal genetic diseases such as Unverricht-Lundborg disease;
neurological diseases associated with intoxications (Cadmium poisoning, inhalation of n-hexane, pesticides, herbicides), associated with treatments (radiotherapy) or disorders of genetic origin (Wilson""s disease).
impotence linked to diabetes;
all the pathologies characterized by an excessive production or a dysfunction of nitrogen monoxide and/or the metabolism of glutathione and of the redox status of the thiol groups.
In all these pathologies, there is experimental evidence demonstrating the involvement of nitrogen monoxide or of a dysfunction of the metabolism of glutathione (Kerwin et al., Nitric oxide: a new paradigm for second messengers, J. Med. Chem. 38, 4343-4362, 1995; Packer et al., Alpha-lipoic acid as biological antioxidant, Free Radical Biology and Medicine 19, 227-250, 1995). This is the case in particular in Parkinson""s disease which illustrates the invention (Beal M F, Excitotoxicity and nitric oxide in Parkinson""s disease pathogenesis. Ann. Neurol. 44[Suppl 1], S110-S114, 1998; Donato et al., Gluthathione in Parkinson""s disease: a link between oxidative stress and mitochondrial damage. Ann. Neurol. 32, S111-S115, 1992). In this context, medicaments which can inhibit the formation of nitrogen monoxide or re-establish the biological functionality of the thiol groups or glutathione can have beneficial effects.
Moreover, in earlier patents, the inventors have already described NO Synthase inhibitors and their use (U.S. Pat. Nos. 5,081,148; 5,360,925) and more recently the combination of these inhibitors with products having antioxidant or antiradicular properties (PCT Patent Application WO/09653). They have also described derivatives of amidines in PCT Patent Applications WO 98/42696 and WO 98/58934 and of the derivatives of aminopyridines in the PCT Patent Application WO 00/02860. These derivatives of amidines or aminopyridines have the characteristic of being both NO Synthase inhibitors and ROS inhibitors
A subject of the present invention is new derivatives of lipoic acid, their preparation and their use in therapeutics.
Therefore the invention relates to a product of general formula (I), characterized in that it comprises the products of sub-formulae (I)a and (I)b 
in which
R1 and R2 represent independently a hydrogen atom or a linear or branched alkyl radical with 1 to 6 carbon atoms;
A represents one of the xe2x80x94(CH2)mxe2x80x94NR3CO(CH2)nxe2x80x94, xe2x80x94(CH2)mxe2x80x94CONR3xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)mxe2x80x94NR3xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)mxe2x80x94CONR3xe2x80x94(CH2)pxe2x80x94NR4xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)mxe2x80x94NR3xe2x80x94COxe2x80x94N4xe2x80x94CH2)nxe2x80x94 or xe2x80x94(CH2)mxe2x80x94 radicals, m and n being integers from 0 to 6, p being an integer from 2 to 6, and R3 and R4 representing independently a hydrogen atom or a linear or branched alkyl radical with 1 to 6 carbon atoms;
X represents a 
xe2x80x83radical, in which the T group, which is attached to the Y group, represents a xe2x80x94(CH2)ixe2x80x94 radical in which i represents an integer comprised between 0 and 6, and R5 represents a hydrogen atom, a linear or branched alkyl radical having 1 to 6 carbon atoms or a xe2x80x94(CH2)mxe2x80x94Q radical in which Q represents a halogen atom or a hydroxy, cyano, amino, alkoxy, alkylthio, alkylamino or dialkylamino radical, or also R5 represents a heterocycle with 5 to 6 members the heterocyclic members of which are chosen from the xe2x80x94Oxe2x80x94, xe2x80x94N(R6)xe2x80x94 and xe2x80x94Sxe2x80x94 radicals, R6 representing a hydrogen atom, a linear or branched alkyl having 1 to 6 carbon atoms or the bond to the phenyl ring of the X radical;
or also X represents a xe2x80x94(CH2)qxe2x80x94 radical in which q represents an integer from 0 to 6;
and finally Y represents one of the 
xe2x80x83radicals in which:
B represents a linear or branched alkyl radical having 1 to 6 carbon atoms, carbocyclic or heterocyclic aryl with 5 or 6 members containing 1 to 4 heteroatoms chosen from O, S, N and in particular the thiophene, furane, pyrrole or thiazole radicals, the aryl radical being optionally substituted by one or more groups chosen from the linear or branched alkyl, alkenyl or alkoxy radicals having 1 to 6 carbon atoms, or B represents NR8R9, in which R8 and R9 represent, independently, a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms, or one of R8 and R9 represents a nitro radical while the other represents a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms, or also R8 and R9 together form with the nitrogen atom a non-aromatic heterocycle with five to six members, the elements of the chain being chosen from a group composed of xe2x80x94CH2xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, or also B represents an SR10 radical in which R10 represents a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms, and R7 represents a hydrogen atom or a linear or branched alkyl radical with 1 to 6 carbon atoms;
or a salt of a product of general formula (I).
Preferably, when R5 represents a heterocycle with 5 to 6 members, R5 will be one of the following heterocycles: pyrrole, imidazole, pyrazole, triazole, thiazolidine, pyrrolidine, piperidine, piperazine, N-alkyl-piperazine, thiomorpholine, morpholine, azetidine.
Moreover, the invention relates in particular to the products of general formula (I) defined previously, in which the following characteristics are found, independently:
A represents one of the xe2x80x94(CH2)mxe2x80x94NR3COxe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)mxe2x80x94CONR3xe2x80x94(CH2)nxe2x80x94 or xe2x80x94(CH2)mxe2x80x94NR3xe2x80x94COxe2x80x94NR4xe2x80x94(CH2)n radicals m representing an integer from 0 to 4 and n an integer from 0 to 6, and R3 and R4 representing independently a hydrogen atom or a linear or branched alkyl radical with 1 to 6 carbon atoms;
X represents the 
xe2x80x83radical, in which the T group, which is attached to the Y group, represents a xe2x80x94(CH2)ixe2x80x94 radical in which i represents 0 or 1, and R5 represents a hydrogen atom, a linear or branched alkyl radical having 1 to 6 carbon atoms or a xe2x80x94(CH2)mxe2x80x94Q radical in which Q represents a halogen atom or a hydroxy, cyano, amino, alkoxy, alkylamino or dialkylamino radical, or R5 represents a heterocycle with 5 to 6 members the heterocyclic members of which are chosen from the xe2x80x94Oxe2x80x94, xe2x80x94N(R6)xe2x80x94 and xe2x80x94Sxe2x80x94 radicals, R6 representing a hydrogen atom, a linear or branched alkyl having 1 to 6 carbon atoms or the bond to the phenyl ring of the X radical; or
Y represents the 
xe2x80x83radical, in which B represents a linear or branched alkyl radical having 1 to 6 carbon atoms, a carbocyclic or heterocyclic aryl radical with 5 or 6 members containing 1 to 4 heteroatoms chosen from O, S, N and in particular the thiophene, furane, pyrrole or thiazole radicals, the aryl radical being optionally substituted by one or more groups chosen from the linear or branched alkyl, alkenyl or alkoxy radicals having 1 to 6 carbon atoms.
More particularly, the invention relates to the following products described in the examples (sometimes in the form of salts):
xe2x80x94N-{4-[[(2-thienyl)(imino)methyl]amino]phenyl}-1,2-dithiolane-3-pentanamide;
xe2x80x94N-{2-{4[[(2-thienyl)(imino)methyl]amino]phenyl}ethyl}-1,2-dithiolane-3-pentanamide;
xe2x80x94N-{2-{4[[(2-thienyl)(imino)methyl]amino]phenyl}ethyl}-1,2-dithiolane-3-acetamide;
xe2x80x94N-[4-(6-amino-4-methyl-2-pyridinyl)butyl]-1,2-dithiolane-3-pentanamide;
xe2x80x94N-[4-(6-amino-4-methyl-2-pyridinyl)butyl]-1,2-dithiolane-3-acetamide;
xe2x80x94N-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-2-(1,2-dithiolan-3-yl)acetamide;
xe2x80x94N-(4-{[amino(2-thienyl)methylidene]amino}benzyl)-5-(1,2-dithiolan-3-yl)pentanamide;
xe2x80x94N-(5-{[amino(2-thienyl)methylidene]amino}-2-methoxyphenyl)-5-(1,2-dithiolan-3-yl)pentanamide;
xe2x80x94N-[5-{[amino(2-thienyl)methylidene]amino}-2-(dimethylamino)benzyl]-5-(1,2-dithiolan-3-yl)pentanamide;
xe2x80x94N-[5-{[amino(2-thienyl)methylidene]amino}-2-(1H-pyrrol-1-yl)benzyl]-5-(1,2-dithiolan-3-yl)pentanamide;
and the salts of these compounds.
Moreover, the invention offers a certain number of processes for accessing the products of general formula (I) described above, processes the preferred conditions of which are described hereafter.
Therefore the invention relates in particular to a process for the preparation of an amidine of general formula (I) as defined previously, characterized in that the intermediate of general formula (II). 
in which A and X are as defined above, is reacted with the intermediate of general formula (I.i) 
in which B is as defined above and L represents a parting group, for example an alkoxy, alkylthio, sulphonic acid, halide, aryl alcohol or tosyl radical.
Moreover, the invention relates to a process for the preparation of a compound of general formula (I) in which A represents a xe2x80x94(CH2)mxe2x80x94CONR3xe2x80x94(CH2)nxe2x80x94 radical as defined previously, characterized in that the intermediate of general formula (VII)a represented below 
R3, X and Y being as defined above and Axe2x80x2 representing the xe2x80x94(CH2)nxe2x80x94 radical, n being as defined above, is reacted with the compound of general formula (I.vi) 
m being as defined above.
Moreover, the invention relates to a process for the preparation of a compound of general formula (I) in which A represents a xe2x80x94(CH2)mxe2x80x94NR3COxe2x80x94NR4xe2x80x94(CH2)n radical as defined previously, characterized in that the intermediate of general formula (VII)b represented below 
R4, X and Y being as defined above and Axe2x80x2 representing the xe2x80x94(CH2)nxe2x80x94 radical, n being as defined above, is reacted with the compound of general formula (I.vi) 
m being as defined above, and with diphenylphosphorylazide in the presence of a base such as for example triethylamine.
The invention also relates to a process for the preparation of a compound of general formula (I) in which B is an amine, characterized in that the intermediate of general formula (II) 
in which A and X are as defined above is reacted,
a) with the intermediate of general formula (I.ii) 
xe2x80x83in which L represents a parting group, for example an alkoxy, alkylthio, sulphonic acid, halide, aryl alcohol or tosyl radical,
b) or with the intermediate of general formula (I.iii) 
xe2x80x83in which L represents a parting group, for example an alkoxy, alkylthio, sulphonic acid, halide, aryl alcohol or tosyl radical, and Gp a protective group of carbamate type, for example the t-butoxycarbonyl group, this reaction being followed, in the case where reaction with a compound of general formula (I.iii) is chosen, by hydrolysis in the presence of a strong acid, for example trifluoroacetic acid,
c) or with the derivative of formula (I.iv) (N-methyl-Nxe2x80x2-nitro-N-nitrosoguanidine) 
d) or finally with the derivative of formula (I.v) in which Gp represents a protective group 
In certain cases, the compounds according to the present invention can comprise asymmetrical carbon atoms, and therefore have two possible enantiomeric forms, i.e. xe2x80x9cRxe2x80x9d and xe2x80x9cSxe2x80x9d configurations. The present invention includes the two enantiomeric forms and all combinations of these forms, including the racemic xe2x80x9cRSxe2x80x9d mixtures. In an effort to simplify matters, when no specific configuration is indicated in the structural formulae, it should be understood that the two enantiomeric forms and their mixtures are represented.
Moreover, in the present application, unless otherwise specified, by alkyl is meant a linear or branched alkyl radical comprising 1 to 6 carbon atoms. By alkenyl, unless otherwise specified, is understood a linear or branched alkyl radical comprising 1 to 6 carbon atoms and having at least one unsaturation (double bond).
By, alkylthio, alkoxy, alkylamino, dialkylamino and alkenyl radicals are meant the alkylthio, alkoxy, alkylamino, dialkylamino and alkenyl radicals respectively the alkyl radical of which has the meaning indicated previously.
By linear or branched alkyl radical having 1 to 6 carbon atoms is meant in particular the methyl, ethyl, propryl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl, neopentyl, isopentyl, hexyl, isohexyl radicals. By halogen is meant the fluorine, chlorine, bromine or iodine atoms.
A subject of the invention is also, as medicaments, the compounds described previously or their pharmaceutically acceptable salts. It also relates to pharmaceutical compositions containing these compounds or their pharmaceutically acceptable salts, and the use of these compounds or of their pharmaceutically acceptable salts for producing medicaments intended to inhibit neuronal NO synthase or inductible NO synthase, to regenerate antioxidants which can be natural or synthetic, or to provide the double function of NO synthase inhibition and the regeneration of antioxidants.
By pharmaceutically acceptable salt is meant in particular addition salts of inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulphate, phosphate, diphosphate and nitrate, or of organic acids, such as acetate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulphonate, p-toluenesulphonate, pamoate, oxalate and stearate. The salts formed from bases such as sodium or potassium hydroxide also fall within the scope of the present invention, when they can be used. For other examples of pharmaceutically acceptable salts, reference can be made to xe2x80x9cPharmaceutical saltsxe2x80x9d, J. Pharm. Sci. 66:1 (1977).
A subject of the invention is also the use of a product of general formula (I) or of a pharmaceutically acceptable salt of this product in order to produce a medicament intended to treat pathologies in which nitrogen monoxide and/or the redox status of thiol groups are involved, pathologies such as disorders of the central or peripheral nervous system particularly well represented by Parkinson""s disease, cerebrovascular disorders, proliferative and inflammatory diseases, vomiting, septic shock, pathologies resulting from radioactive irradiations, solar radiations or organ transplants, autoinmune and autosomal diseases, cancer and all the pathologies characterized by a production or a dysfunction involving nitrogen monoxide and/or involving the redox status of thiol groups.
A subject of the invention is also the use of a product of general formula (I) or of a pharmaceutically acceptable salt of this product, in order to produce a medicament intended to treat cerebrovascular disorders such as migraine, cerebral infarctions of ischemic or hemorragic origin, ischemias and thromboses.
Finally a subject of the invention is the use of a product of general formula (I) or of a pharmaceutically acceptable salt of this product in order to produce a medicament intended to treat disorders of the central or peripheral nervous system such as neurodegenerative diseases, pain, cerebral and bone marrow traumas, addiction to opiates, alcohol and addictive substances, erective and reproductive disorders, cognitive disorders, encephalopathies, depression, anxiety, schizophrenia, epilepsy, sleeping disorders and eating disorders.
The pharmaceutical compositions can be in the form of a solid, for example powders, granules, tablets, capsules, liposomes or suppositories. Appropriate solid supports can be for example calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine and wax.
The pharmaceutical compositions containing a compound of the invention can also be presented in the form of a liquid, for example, solutions, emulsions, suspensions or syrups. Appropriate liquid supports can be, for example, water, organic solvents such as glycerol or glycols, as well as their mixtures, in varying proportions, in water.
A medicament according to the invention can be administered by topical, oral or parenteral route, by intramuscular injection, etc.
The envisaged administration dose for a medicament according to the invention is comprised between 0.1 mg and 10 g according to the type of active compound used.
In accordance with the invention, the compounds of general formula (I) can be prepared by the process described below.

The compounds of general formula (I) can be prepared from the intermediates of general formula (II), (III) and (IV) according to Diagram 1 where A, B, X and Y, are as defined above and Gp is a protective group of carbamate type. 
The aniline and amine derivatives of general formula (II), can be condensed with the compounds of general formula (I.i), in which L represents a parting group (in particular an alkoxy, alkylthio, sulphonic acid, halide, aryl alcohol or tosyl radical), in order to produce the final compounds of general formula (I) of substituted amidine type (cf. Diagram 1). For example, for B=thiophene, the derivatives of general formula (II) can be condensed with S-methylthiophene thiocarboxamide hydroiodide, prepared according to a method in the literature (Ann. Chim. (1962), 7, 303-337). The condensation can be carried out by heating in an alcohol (for example in methanol or isopropanol), optionally in the presence of DMF at a temperature preferably comprised between 50 and 100xc2x0 C. for a duration generally comprised between a few hours and overnight.
In the case where B=SR10, for example Sxe2x80x94CH3, this can be prepared by the condensation of the amines or anilines of general formula (II) with the isothiocyanate (I.v) in which Gp represents a protective group such as for example the benzoyl group. Then deprotection is carried out by cleavage of the protective group under appropriate conditions and the thiourea formed is finally treated with, for example, a halogenoalkane in order to produce the final compounds of general formula (I).
In the case where B=NR8R9, the final compounds of general formula (I) are guanidines. These can be prepared, for example, by the condensation of the amines or anilines of general formula (II) with the derivatives of general formula (I.ii) or (I.iii). The reagents of general formula (I.ii) in which L represents, for example, a pyrazole ring are condensed with the amines of general formula (II) according to the conditions described in the literature (J. Org. Chem. (1992) 57, 2497-2502) similarly for the reagents of general formula (I.iii) in which L represents, for example, a pyrazole ring and Gp the tBuOCO group (Tetrahedron Lett. (1993) 34 (21), 3389-3392) or when L represents the xe2x80x94Nxe2x80x94SO2xe2x80x94CF3 group and Gp the tBuOCO group (J. Org. Chem. (1998) 63, 3804-3805). During the final stage of the synthesis, deprotection of the guanidine function is carried out in the presence of a strong acid such as for example trifluoroacetic acid.
In the case where B=xe2x80x94NHNO2 the final compounds of general formula (I) can be prepared, for example, by the condensation of the amines or anilines of general formula (II) with the reagent of formula (I.iv) (N-methyl-Nxe2x80x2-nitro-N-nitrosoguanidine) according to the conditions described in the literature. (J. Amer. Chem. Soc. (1947), 69, 3028-3030).
The compounds of general formula (I)b, are obtained from the compounds of general formula (I)a where A, X and Y are as defined above. The conversion of the lipoic compounds of general formula (I)a to dihydrolipoic derivatives of general formula (I)b in which R1xe2x95x90R2=H is carried out in an alcoholic solvent such as, for example, methanol in the presence of a reducing agent such as for example NaBH4, NaBH3CN or LiAlH4. The compounds of general formula (I)b for which R1 and R2 are not H are prepared by reacting the compounds of general formula (I)b in which R1=R2=H with a compound of formula R1-Hal and/or R2-Hal (Hal halogen atom) where R1 and R2 are as defined above and the halogen atom is a parting group. The reaction is carried out, for example, in an appropriate solvent such as THF, acetone, ethyl acetate in the presence of a base such as K2CO3 or triethylamine, in order to produce the intermediates of general formula (I)b.
The intermediates of general formula (II), are obtained from the cleavage of a protective group (Gp) or by reduction of a nitro group.
The intermediates of general formula (II), in which A and X are as defined above, can be prepared from the intermediates of general formula (III) or (IV), Diagram 1, which are compounds containing respectively a protected amine or aniline (NHGp) in the form, for example, of a carbamate or a nitro group. In the particular case of the BOC groups, these are deprotected in a standard fashion using TFA or HCl, in order to finally produce the primary amines and anilines of general formula (II). The reduction of the nitro function of the intermediates of general formula (IV), Diagram 1, in which A, and X are as defined above, is carried out, for example, by heating the product in an appropriate solvent such as ethyl acetate with a little ethanol in the presence of SnCl2 (J. Heterocyclic Chem. (1987), 24, 927-930; Tetrahedron Letters (1984), 25 (8), 839-842) in the presence of SnCl2/Zn (Synthesis. (1996), 9,1076-1078), using NaBH4xe2x80x94BiCl3 (Synth. Com. (1995)25 (23),3799-3803) in a solvent such as ethanol, or then by using Raney Ni with hydrazine hydrate added to it (Monatshefte fxc3xcr Chemie, (1995), 126, 725-732), or using indium in an ethanol and ammonium chloride mixture under reflux (Synlett (1998) 9, 1028). Then, the double reduction product is reoxidized in the presence of ferric chloride (FeCl3) (Synlett (1991) 10, 71 7-718) or iodine (Tetrahedron Letters. (1997), 38 (33), 5785-5788) in order to finally produce the amines and anilines again containing the dithiolane of general formula (II).
The carboxamides of general formula (III) and (IV), Diagram 2, in which A, X, R3 and m are as defined above, are prepared by condensation of the acids of general formula (I.vi) with the mono-protected amines or anilines of general formula (V) or the nitro derivatives of general formula (VI) in which Axe2x80x2 represents the xe2x80x94(CH2)nxe2x80x94 radical. The Rx radical, in the synthesis diagrams of the present Application, signifies, depending on the case, R3 or R4. The carboxamides bonds are formed under the standard conditions of peptide synthesis (M. Bodanszky and A. Bodanszky, The Practice of Peptide Synthesis, 145 (Springer-Verlag, 1984)) in THF, dichloromethane or DMF in the presence of a coupling reagent such as dicyclohexylcarbodiimide (DCC), 1,1xe2x80x2-carbonyldiimidazole (CDI) (J. Med. Chem. (1992), 35 (23), 4464-4472) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC or WSCI) (John Jones, The chemical synthesis of peptides, 54 (Clarendon Press, Oxford, 1991)) or in the presence of isobutyl chloroformate and N-methylmorpholine (Org. Prep. Proced. Int., (1975), 35, 215). The syntheses of the carboxylic acids of general formula (I.vi) and the amines/anilines of general formula (V) and (VI), which are not commercially available, are described hereafter. 
The compounds of general formula (I) can also be prepared from the intermediates of general formula (VII), (VIIII), (IX) and (X) according to Diagram 3 in which A, B, X and Y are as defined above, Axe2x80x2 represents the xe2x80x94(CH2)nxe2x80x94 radical, the Rx radical signifies, depending on the case, R3 or R4, and Gp is a protective group, for example a protective group of carbamate type. 
The carboxamides of general formula (I), Diagram 4, in which Axe2x80x2, X, R3, Y and m are as defined above, are prepared by condensation of the acids of general formula (I.vi) with the amines/anilines of general formula (VII). The carboxamide bonds are formed under standard conditions of peptide synthesis (M. Bodanszky and A. Bodanszky, The Practice of Peptide Synthesis, 145 (Springer-Verlag, 1984)) in THF, dichloromethane or DMF in the presence of a coupling reagent such as dicyclohexylcarbodiimide (DCC), 1,1xe2x80x2-carbonyldiimidazole (CDI) (J. Med. Chem. (1992), 35 (23), 4464-4472) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC or WSCI) (John Jones, The chemical synthesis of peptides, 54 (Clarendon Press, Oxford, 1991)) or in the presence of isobutyl chloroformate and N-methylmorpholine (Org. Prep. Proced Int., (1975), 35, 215). The syntheses of the carboxylic acids of general formula (I.vi) which are not commercially available are described hereafter. 
The ureas of general formula (I), Diagram 5, in which m, Axe2x80x2, R4, X and Y are as defined above, are prepared by condensation of the acids of general formula (I.vi) with the amines/anilines of general formula (VII) in a solvent such as toluene in the presence of diphenylphosphorylazide (DPPA) and a base such as for example triethylamine, preferably for 2 to 3 hours and by heating, preferably at a temperature of 40 to 110xc2x0 C., for example at a temperature of 80xc2x0 C. 
The compounds of general formula (VII), are obtained by cleavage of a protective group. The compounds of general formula (VII), in which Rx, Axe2x80x2, X and Y are as defined above, can be prepared from the compounds of general formula (VIII), Diagram 3, which are compounds containing a protected amine (NGp) in the form, for example, of a carbamate. In the particular case of the BOC groups, these are deprotected in a standard fashion using trifluoroacetic acid (TFA) or HCl, in order to finally produce the amines of general formula (VII).
The compounds of general formula (VIII) can be prepared from the intermediates of general formula (IX) and (X) according to Diagram 3 where B, Axe2x80x2, X, Y and Rx are as defined above and Gp is a protective group, for example of carbamate type.
The aniline/amine derivatives of general formula (IX) can be condensed with the compounds of general formula (I.i), (I.ii), and (I.iii), in which L represents a parting group, or the compounds of general formula (I.iv) and (I.v), as previously described for the compounds of general formula (I) in Diagram 1, in order to finally produce the compounds of general formula (VIII), Diagram 3. In the case where R3 represents the 2-hydroxy-4,6-dimethoxybenzyl radical and Gp represents t-butoxycarbonyl (BOC), these conditions give rise to N-debenzylation in situ, in order to directly produce the compounds of general formula (VIII), Diagram 6. 
The compounds of general formula (IX), are obtained from the reduction of a nitro group of the compounds of general formula (X). The reduction of the nitro function of the compounds of general formula (X), Diagram 3, in which Rx, Axe2x80x2 and X are as defined above, is carried out, for example, by heating the product in an appropriate solvent such as ethyl acetate with a little ethanol in the presence of SnCl2 (J. Heterocyclic Chem. (1987), 24, 927-930; Tetrahedron Letters (1984), 25 (8), 839-842) in the presence of SnCl2/Zn (Synthesis. (1996), 9, 1076-1078) or using NaBH4-BiCl3 (Synth. Com. (1995) 25 (23), 3799-3803) in a solvent such as ethanol, or then by using Raney Ni with hydrazine hydrate added to it (Monatshefte fxc3xcr Chemie, (1995), 126, 725-732), or also using indium in a mixture of ethanol and ammonium chloride under reflux (Synlett (1998) 9, 1028), in order to finally produce the primary amines and anilines of general formula (IX).
The preparation of the compounds of general formula (X) which are not commercially available is described hereafter.

The compounds of general formula (I) in which A, X, Y and R7 are as defined above, can be prepared from the intermediates of general formula (II) according to the procedure illustrated in Diagram 7. 
The final molecules of general formula (I) are obtained after cleavage of the 2,5-dimethylpyrrole protective group of the compounds of general formula (II) by heating in the presence of hydroxylamine hydrochloride, at a temperature which varies from 60xc2x0 C. to 100xc2x0 C., in a solvent such as for example ethanol according to an experimental protocol described in J. Chem. Soc. Perkin Trans. (1984), 12, 2801-2807.
The compounds of general formula (II) can be prepared according to the following synthesis diagrams:
1.1) The synthetic precursors which lead to the intermediates of general formula (II) are prepared, Diagram 8, from the compounds of general formula (II.1), such as for example 2-(2,5-dimethylpyrrol-1-yl)-4,6-dimethylpyridine. This is obtained from commercial 6-amino-2,4-lutidine according to a experimental protocol described in J. Chem. Soc. Perkin Trans., (1984), 12, 2801-2807. Treatment of the compounds of general formula (II.1) with a strong base such as, for example, n-BuLi, at a temperature which varies from xe2x88x9250xc2x0 C. to xe2x88x9230xc2x0 C. in an anhydrous solvent such as ethyl ether, under an inert atmosphere and optionally in the presence of N,N,Nxe2x80x2,Nxe2x80x2-tetramethylethylenediamine allows the lithiated derivative to form (intermediate (II.2)) which in the presence of an electrophile E+ leads to the adducts of general formula (II.x). 
1.2) Among the electrophiles E+ which can react with the lithiated types of general formula (II.2), the protected halogeno-amines are for example found. The amines of general formula (II.3) are prepared from intermediate (II.2) which is condensed, for example, on protected halogeno-amines (for example in the form of silylated derivatives or phthalimides) under conditions which have been described previously. The amines of general formula (II.4) are finally obtained after deprotection under conditions described in the literature (T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Second edition (Wiley-Interscience, 1991)). 
The carboxamides of general formula (II), in which m, R3, Axe2x80x2 and R7 are as defined above, can also be prepared, Diagram 10, by condensation of the carboxylic acids of general formula (I.vi) with the amines of general formula (II.4) under conditions which have been described previously. Synthesis of the carboxylic acids of general formula (I.vi), which are not commercially available, is described hereafter. 
The acids of general formula (I.vi) which are not commercially available, in which m is as defined above are accessible via methods described in the literature. For example, trisnorlipoic acid is obtained in 5 stages according to an experimental protocol described in Tetrahedron Letters (1997), 38 (33), 5785-5788.
When X represents a xe2x80x94(CH2)qxe2x80x94 radical, the selectively mono-protected primary amines of general formula (V) and (IX) in which R3 represents H are accessible via methods described in the literature, (for example: Synthesis (1984), 12, 1032-1033; Synth. Commun. (1990), 20 (16), 2559-2564; J. Amer. Chem. Soc. (1993), 115 (9), 3548-15 3557; J. Med Chem. (1989), 32 (2), 391-396). J. Amer. Chem. Soc. (1995), 117 (11). 3308-3309). The primary nitro-amines of general formula (VI) in which R3 represents H are accessible via methods described in the literature (for example: J. Chem. Soc. (1947), 1487).
When X represents a phenylene radical and n and R5 are as defined above, the amines/anilines of general formula (V) in which R3 represents H are accessible via methods illustrated in Diagram 2.1 hereafter. 
The compounds of general formula (V), Diagram 2.1, are prepared from the nitro-amines or nitro-anilines of general formula (VI.1). The protection of the amine or aniline function is carried out for example, in an appropriate solvent such as dioxane or dichloromethane or acetonitrile in the presence of Fmoc-Cl (Tetrahedron Letters. (1989), 30 (11), 1401-1404) or (Boc)2, or of precursors of other protective groups (Gp) known to a person skilled in the art in order to produce the compounds of general formula (V.2) (or the compounds of general formula (X)). The reduction of the nitro function of the intermediates of general formula (V.2) is generally carried out by catalytic hydrogenation, in ethanol, in the presence of 10% Pd/C or by other methods described previously, in order to produce the anilines (V.3) (or the compounds of general formula (IX)). Protection of the aniline function of general formula (V.3) is carried out, for example, in the presence of Fmoc-Cl or (Boc)2 or of precursors of other protective groups (Gp) known to a person skilled in the art, it being understood that Gp1xe2x89xa0Gp2, Diagram 2.1. The last stage of the synthesis consists of regenerating the primary amine by mono-deprotection, for example, when Gp1=Fmoc, the deprotection is carried out, for example, in an appropriate solvent such as DMF or dioxane, in the presence of a base such as piperidine, morpholine, DMAP, or diisopropylethylamine (Tetrahedron Letters. (1989), 30 (11), 1401-1404). When Gp2=Boc, these are deprotected in a standard fashion using trifluoroacetic acid or HCl, in order to finally produce the mono-protected anilines of general formula (V).
The compounds of general formula (IX) and (X) for which R3 represents the 2-hydroxy-4.6-dimethoxyphenol radical, Gp represents the Boc group and n and R5 are as defined above, are prepared from the nitro-amines or nitro-anilines of general formula (VI.1), Diagram 6.1. 
The compounds of general formula (IX) and (X) are prepared, Diagram 6.1, by condensation of 2-hydroxy-4,6-dimethoxybenzaldehyde with an amine/aniline of general formula (VI.1) in a reducing medium. The reaction takes place in an alcoholic solvent such as, for example, methanol, in the presence of a reducing agent such as, for example, NaBH4 or NaBH3CN. The protection of the secondary amine formed is then carried out in a standard fashion with (Boc)2 in dichloromethane in order to produce the compounds of general formula (X). The reduction of the nitro function of the compounds of general formula (X) is carried out by catalytic hydrogenation, in ethanol, in the presence of 10% Pd/C in order to produce the anilines (IX).
When X represents a phenylene radical and R5 represents a heterocycle with 5 to 6 members comprising a nitrogen atom (het) or a group comprising a heteroatom W (group referred to as Wxcex1xcex2 where W=O, N or S, xcex1 representing alkyl and xcex2 not existing when W=O or S or xcex2 representing H or alkyl when W=N), Diagrams 3.1 and 3.2, the amines/anilines of general formula (X) which are not commercially available in which R3 represents H are accessible via methods described in the literature (for example: J. Med. Chem. (1980), 23, 973-975; J. Med. Chem. (1990), 33, 633-641; Chem. Heterocycl. Compd. (EN). (1969), 5, 683-687; J. Org. Chem. USSR. (EN) (1989), 3, 599-600; J. Med. Chem. (1994). 37, 467-475; J. Med. Chem. (1999), 42, 4362-4379). For example, the compounds of general formula (X) can be prepared by the methods illustrated in Diagram. 3.1. 
The compounds of general formula (X), Diagram 3.1, in which n, het and Wxcex1xcex2 are as defined above are prepared from the halogeno-nitrobenzonitriles of general formula (X.2). Reduction of the nitrile function of the intermediates of general formula (X.2), Diagram 3.1, is carried out, for example, in an appropriate solvent such as ether or THF, in the presence of diborane or LAH. The halogeno-nitroanilines/amines (X.3) formed are then protected in the form of Boc (X.4) or of other protective groups (Gp) known to a person skilled in the art then the compounds of general formula (X.4) are subjected to a nucleophilic substitution by a heterocyclic group (het) in a solvent such as DMSO or DMF, in the presence of a base such as K2CO3, KOH or NaOH, in order to produce the intermediates of general formula (X).
Alternatively, the compounds of general formula (X) as defined previously can be prepared, according to a method based on that shown in Diagram 3.2 hereafter: 
The compounds of general formula (X), Diagram 3.2, in which R5 represents a heterocycle with 5 to 6 members comprising a nitrogen atom (het) or a group comprising a heteroatom W (Wxcex1xcex2 as defined previously), are prepared from halogeno-nitrobernzonitriles of general formula (X.2). The compounds of general formula (X.2) are subjected to a nucleophilic substitution by the appropriate reagent in a solvent such as DMSO or DMF, in the presence of a base such as K2CO3, KOH or NaOH, in order to produce intermediates of general formula (X.5).
The reduction of the nitrile function of the intermediates of general formula (X.5), Diagram 3.2, is carried out, for example, in an appropriate solvent such as ether or THF, in the presence of diborane or LAH. The halogeno-nitroanilines/amines (X.6) formed are then protected in the form of Boc or other protective groups (Gp) known to a person skilled in the art in order finally to produce intermediates of general formula (X), Diagram 3.2.